In many disease states, the body lacks or loses control over angiogenesis and its ability to regulate or limit vascularization. Excessive angiogenesis and subsequent vascularization occurs in diseases such as cancer, macular degeneration, diabetic retinopathy, arthritis and psoriasis. In these conditions, new blood vessels feed diseased tissues destroy normal tissues, and in the case of cancer, the new vessels allow tumor cells to escape into the circulation and lodge in other organs (tumor metastasis).
Expansion of tumor volume beyond a certain phase requires the induction of new capillary blood vessels. For example, pulmonary micrometastases in the early pre-vascular phase in mice would be undetectable except by high power microscopy on histological sections. Further indirect evidence supporting the concept that tumor growth is angiogenesis dependent is found in U.S. Pat. Nos. 5,639,725, 5,629,327, 5,792,845, 5,733,876, and 5,854,205.
Neovascularization in the eye is the basis of severe ocular diseases such as age-related macular degeneration (AMID) and Diabetic retinopathy. AMD is the most common cause of legal, irreversible blindness in patients aged 65 and over in the US, Canada, England, Wales, Scotland and Australia. Although the average age of patients when they lose central vision in their first eye is about 65 years, some patients develop evidence of the disease in their fourth or fifth decade of life. Approximately 10% to 15% of patients manifest the exudative (wet) form of the disease. Exudative AMD is characterized by angiogenesis and the formation of pathological neo-vasculature. The disease is bilateral with accumulating chances of approximately 10% to 15% per annum of developing the blinding disorder in the fellow eye.
Diabetic retinopathy is a complication of diabetes that occurs in approximately 40 to 45 percent of those diagnosed with either Type I or Type II diabetes. Diabetic retinopathy usually affects both eyes and progresses over four stages. The first stage, mild non-proliferative retinopathy, is characterized by micro-aneurysms in the eye. Small areas of swelling in the capillaries and small blood vessels of the retina occurs. In the second stage, moderate non-proliferative retinopathy, the blood vessels that supply the retina become blocked. In severe non-proliferative retinopathy, the third stage, the obstructed blood vessels lead to a decrease in the blood supply to the retina, and the retina signals the eye to develop new blood vessels (angiogenesis) to provide the retina with blood supply. In the fourth and most advanced stage, proliferative retinopathy, angiogenesis occurs, but the new blood vessels are abnormal and fragile and grow along the surface of the retina and vitreous gel that fills the eye. When these thin blood vessels rupture or leak blood, severe vision loss or blindness can result.
There is a need for the discovery and development of additional anti-angiogenic agents that may be used alone, or in combination with known angiogenic agents, in order to treat or prevent angiogenesis-related disorders.
Many diseases and conditions whose treatment is sought would benefit from the ability to mitigate cell or tissue adhesion or vascularization within a desired site in a body of a subject.